Impotence is the consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse. It has recently been estimated that approximately 10 million American men are impotent (R. Shabsigh et al., "Evaluation of Erectile Impotence," Urology 32:83-90 (1988); W. L. Furlow, "Prevalence of Impotence in the United States," Med. Aspects Hum. Sex. 19:13-6 (1985)). Impotence is recognized to be an age-dependent disorder, with an incidence of 1.9 percent at 40 years of age and 25 percent at 65 years of age (A. C. Kinsey et al., "Age and Sexual Outlet," in Sexual Behavior in the Human Male; A. C. Kinsey et al., eds., Philadelphia, Pa.: W. B. Saunders, 218-262 (1948)). In 1985 in the United States, impotence accounted for more than several hundred thousand outpatient visits to physicians (National Center for Health Statistics, National Hospital Discharge Survey, 1985, Bethesda, Md., Departnent of Health and Human Services, 1989 DHHS publication no. 87-1751). Depending on the nature and cause of the problem, treatments include psychosexual therapy, hormonal therapy, administration of vasodilators such as nitroglycerin and .alpha.-adrenergic blocking agents (".alpha.-blockers"), oral administration of other pharmaceutical agents, vascular surgery, implanted penile prostheses, vacuum constriction devices and external aids such as penile splints to support the penis or penile constricting rings to alter the flow of blood through the penis.
A number of causes of impotence have been identified, including vasculogenic, neurogenic, endocrinologic and psychogenic.
Vasculogenic impotence, which is caused by alterations in the flow of blood to and from the penis, is thought to be the most frequent organic cause of impotence. Common risk factors for vasculogenic impotence include hypertension, diabetes, cigarette smoking, pelvic trauma, and the like.
Neurogenic impotence is associated with spinal-cord injury, multiple sclerosis, peripheral neuropathy caused by diabetes or alcoholism and severance of the autonomic nerve supply to the penis consequent to prostate surgery.
Erectile dysfunction is also associated with disturbances in endocrine function resulting in low circulating testosterone levels and elevated prolactin levels.
Impotence can also be a side effect of various classes of drugs, in particular, those that interfere with central neuroendocrine control or local neurovascular control of penile smooth muscle. Krane et al., New England Journal of Medicine 321:1648 (1989). Penile erection requires (1) dilation of the arteries that regulate blood flow to the lacunae of the corpora cavernosum, (2) relaxation of trabecular smooth muscle, which facilitates engorgement of the penis with blood, and (3) compression of the venules by the expanding trabecular walls to decrease venous outflow.
Trabecular smooth muscle tone is controlled locally by adrenergic (constrictor), cholinergic (dilator) and nonadrenergic, noncholinergic (dilator) innervation, and by endothelium-derived vasoactive substances such as vasoactive intestinal polypeptide (VIP), prostanoids, endothelin and nitrous oxide. High sympathetic tone (noradrenergic) is implicated in erectile dysfunction, and, in some patients, the disorder can be successfully treated with noradrenergic receptor antagonists. See, e.g., Krane et al., supra.
There is also evidence that dopaminergic mechanisms are involved in erectile function. For example, pharmacologic agents that elevate the level of brain dopamine or stimulate brain dopamine receptors increase sexual activity in animals (see, e.g., Gessa & Tagliamonte, Life Sciences 14:425 (1974); Da Prada et al., Brain Research 57:383 (1973)).
Administration of L-DOPA, a dopamine precursor, enhances sexual activity in male rats. L-DOPA has been used in the treatment of Parkinsonism and is known to act as an aphrodisiac in some patients (Gessa & Tagliamonte, supra; Hyppa et al., Acta Neurologic Scand. 46:223 (Supp. 43, 1970)). Specific dopamine agonists have been studied for their effects on erectile function. Apomorphine, (n-propyl)norapomorphine, bromocryptine, amantidine, fenfluramine, L-DOPA and various other pharmacological activators of central dopaminergic receptors have been found to increase episodes of penile erection in male rats (Benassi-Benelli et al., Arch. int. Pharmacodyn. 242:241 (1979); Poggioli et al., Riv. di Farm. & Terap. 9:213 (1978); Falaschi et al., Apomorphine and Other Dopaminomimetics, 1:117-121 (Gessa & Corsini, Eds., Raven Press, N.Y.)). In addition, U.S. Pat. No. 4,521,421 to Foreman relates to the oral or intravenous administration of quinoline compounds to treat sexual dysfunction in mammals.
The currently available dopamine agonists, with few exceptions, have found limited use in the treatment of erectile dysfunction because of their peripheral side effects. These effects include nausea and vomiting, postural hypotension, arrhythmias, tachycardia, dysphoria, psychosis, hallucinations, drowsiness and dyskinesias (See, e.g., Martindale The Extra Pharmacopoeia, 31st Ed., pages 1151-1168).
The invention described herein provides a means to avoid the above-mentioned side effects in administering suitable active agents in treating erectile dysfunction. Specifically, the invention relates to methods, pharmaceutical compositions and kits for treating erectile dysfunction, particularly vasculogenic erectile dysfunction. The invention involves transurethral administration of an androgenic agent as will be described in detail herein.
T. M. Mills et al., "Sites of Androgenic Regulation of Cavernosal Blood Pressure During Penile Erection in the Rat," International Journal of Impotence Research 8:29-34 (1996), investigates the role of androgens in regulating erectile blood flow, and proposes a model for further experiments concerning control of the erectile response in rats and other species. U.S. Pat. No. 5,342,834 to Bardin et al. also pertains to androgenic agents and erectile dysfunction, and suggests the administration of androgenic agents "for providing androgen hormone supplementation" such as in the treatment of impotence and infertility. Neither reference discloses or suggests transurethral administration of androgenic or other agents to treat erectile dysfunction.
Transurethral administration of pharmacologically active agents has been described. U.S. Pat. No. 4,478,822 to Haslam et al. relates to a controlled release, thermosetting gel formulation for delivering drugs into a body cavity such as the urethra. U.S. Pat. No. 4,610,868 to Fountain et al. describes a biodegradable lipid matrix composition for administering a drug, optionally through the urethra. Basile et al., "Medical Treatment of Neurogenic Impotence," Sexual Disabilities 12(1):81-94 (1994) describes the intraurethral administration of drugs. While these references mention urethral drug delivery, the potential importance of administering androgenic agents in this manner, to treat erectile dysfunction, is unknown. Applicant is unaware of any art disclosing the effectiveness of transurethral administration of androgenic agents such as testosterone, or testosterone derivatives or analogs, in the treatment or prevention of impotence.
In addition to the aforementioned references, the following documents are of interest insofar as they relate to urethral drug delivery: International Patent Publication No. WO91/16021; U.S. Pat. No. 4,801,587 to Voss et al.; and U.S. Pat. No. 5,242,391 to Place et al. These references relate to the treatment of erectile dysfunction by delivering a vasoactive agent into the male urethra.
The following documents are also of interest insofar as they relate to the treatment of erectile dysfunction by delivering a vasoactive agent locally to the penis.
U.S. Pat. No. 4,127,118 to Latorre describes the injection of vasodilator drugs into the corpora cavemosa of the penis to dilate the arteries that supply blood to the erectile tissues, thereby inducing an erection.
U.S. Pat. No. 5,439,938 to Snyder et al. describes the administration of nitric oxide (NO) synthase inhibitors by direct injection of a drug into the corpora cavemosa, by topical drug administration or transurethral drug administration, for inhibiting penile erection due to priapism and for treating urinary incontinence.
Virag et al., Angiology-Journal of Vascular Diseases (February 1984), pp. 79-87, Brindley, Brit. J. Psychiat. 143:332-337 (1983) and Stief et al., Urology XXXI:483-485 (1988) respectively describe the intracavernosal injection of papaverine (a smooth muscle relaxant), phenoxybenzamine or phentolamine (.alpha.-receptor blockers) and a phentolamine-papaverine mixture to treat erectile dysfunction.
It has now been discovered that transurethral administration of androgenic agents, as provided herein, is extremely effective in the prevention and treatment of erectile dysfunction. While not wishing to be bound by theory, applicant hypothesizes that the high local levels of active agent which are achieved by the present method provide for unexpected success in addressing the problem of male erectile dysfunction, particularly vasculogenic impotence.